The complex circuitry of the mammalian brain enables the execution of fundamental cognitive processes such as learning, speech, and memory. Neural circuits are assembled via specialized sites of cell-cell contact and communication between neurons termed synapses. Aberrant synapse development can have pathological consequences for circuit function as demonstrated by the manifestation of devastating neurological impairments, including epilepsy and autism spectrum disorders. The aim of our research is to define the molecular program that underlies both excitatory and inhibitory synapse development with the goal of contributing to a greater understanding of neural circuit formation and function.

(View full image) Figure 2. mEPSC analysis reveals defects in the development of functional excitatory synapses upon RNAi-mediated knockdown of the genes Rem2, Cadherin-11, Cadherin-13, or Sema4B.

While biochemical and candidate gene approaches have led to the identification of a large number of molecules that function at the synapse, the process of synapse development itself remains poorly understood. Some of the critical questions in the field include:

1. Which proteins are required for excitatory and inhibitory synapse development and what is their mechanism of action?
2. At which specific step in synapse development is the activity of each protein required?
3. How does a neuron maintain the correct balance of excitatory and inhibitory synapses in order to function appropriately within a neural circuit?

We have begun to address these important questions using a novel, forward genetic RNA interference (RNAi)-based screen in cultured hippocampal neurons (Fig. 1) that has identified new molecules required for synapse development. Thus far, we have isolated five new genes that are required for the proper development of excitatory and/or inhibitory synapses (Figs. 2&3).

To investigate the function of the genes isolated in this and future screens, we utilize a combination of molecular, biochemical, and electrophysiological approaches in primary cultures of hippocampal neurons, organotypic hippocampal slice, acute hippocampal slice, and mouse models. In addition, as only 30% of genes in the mammalian genome have an ascribed function, a complete understanding of synapse development and circuit function depends on identifying the full complement of molecules that mediate these important processes. Thus, future screens will focus on isolating molecules that function to regulate the development of either excitatory or inhibitory synapses, or that act as general promoters of synaptic development.

Recent publications

Emerging themes in GABAergic synapse development. Kuzirian MS, Paradis S. Prog Neurobiol. 2011 Jul 20;95(1):68-87. Epub ahead of print. [abstract]

The GTPase Rem2 regulates synapse development and dendritic morphology. Ghiretti AE, Paradis S. Dev Neurobiol. 2011 May;71(5):374-89. doi: 10.1002/dneu.20868. [abstract]

Paradis, S.*, Harrar, D.B.*, Lin, Y., Koon, A.C., Hauser, J.L., Griffith, E.C., Zhu, L., Brass, L.F., Chen, C., Greenberg, M.E. (2007) An RNAi-based Approach Identifies New Molecules Required for Glutamatergic and GABAergic Synapse Development. Neuron 53: 217-232. [abstract]

(View full image) Figure 3. An immunocytochemistry - based assay of inhibitory synapse density demonstrates that Rem2, Cadherin-11, Cadherin-13, Sema4B or Sema4D are required for the proper development of inhibitory synapses.

Flavell, S.W., Cowan, C.W., Kim, T.K., Greer, P.L., Lin, Y., Paradis, S., Griffith, E.C., Hu, L.S., Chen, C., Greenberg, M.E. (2006) Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number. Science 311: 1008-1012. [abstract]

Tolias, K.F., Bikoff, J.B., Burette, A., Paradis, S., Harrar, D., Tavazoie, S., Weinberg, R.J., Greenberg, M.E. (2005) The Rac1-GEF Tiam1 Couples the NMDA Receptor to the Activity-Dependent Development of Dendritic Arbors and Spines. Neuron 45: 525-538. [abstract]

Paradis, S., Sweeney, S.T., Davis, G.W. (2001) Homeostatic Control of Presynaptic Release is Triggered by Postsynaptic Membrane Depolarization. Neuron 30: 737-749

Davis, G.W., Eaton, B., Paradis, S. 2001. Synapse Formation Revisited. Nat. Neurosci. 4: 558-560.

*authors contributed equally

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Last review: August 22, 2011